Although opioid drugs are effective for short-term pain relief, major obstacles remain with long-term use of these drugs. Specifically, the many side effects are associated with the drugs, such as increasing incidents of drug abuse leading to addiction, have hampered opioid drug usage. A probable mechanism for drug addiction involves the activation and alteration in the neural circuitry that normally is involved in pleasure, incentive motivation, and learning, during chronic drug exposure. In addition to dopaminergic inputs from the ventral tegmental area and substantia nigra to the nucleus accumbens and striatum, glutaminergic inputs from the prefrontal cortex, amygdala, and hippocampus also have important roles in chronic drug action. Since the hippocampus is the structure involved in the storage, consolidation, and retrieval of decorative, spatial, and long-term memory, understanding its roles in drug acquisition and relapse, as well as drug reward experiences, has gained importance. Both electrophysiological and morphological plasticity have been observed with the various hippocampal structures during the course of drug exposure. In addition, integration of newborn neurons to the existing circuit within the hippocampus may have pronounced effects on the drug experience. Considering that all addictive drugs have been shown to alter adult neurogenesis, elucidating the mechanism by which opioid drugs regulate adult neurogenesis, and identifying the specific aspect of the drug experience that adult neurogenesis participates in will have a significant impact in understanding the long-term use of opioid drugs. During the course of our studies on ?-opioid receptor (OPRM1) biased agonism, we observed that morphine and fentanyl, two highly prescribed opioids, regulate the microRNA-190 level differentially, leading to differences in NeuroD levels within primary hippocampal neuron cultures. Since NeuroD is the transcription factor involved in differentiation and maturation of neurons, we hypothesize that OPRM1, by controlling miR-190/NeuroD pathway activity, regulates adult neurogenesis in the hippocampus. We further hypothesize that, since morphine and fentanyl are both addictive, differential control of miR-190/NeuroD activity by these two agonists is not involved in the acquisition of addictive behavior, but rather in the consolidation and retrieval of the context memory associated with drug reward. Therefore, the proposed studies are designed: (A) to understand the molecular mechanism involved in morphine and fentanyl biased agonism so as to manipulate the outcomes of this biased agonism; (B) to establish that miR-190/NeuroD regulation is central to the agonists differential regulation of adult neurogenesis in the hippocampus; and (C) to link the regulation of NeuroD activities and neurogenesis with the extinction of conditioned place preference induced by opiate agonists. From these studies, we anticipate that, by manipulating the miR-190/NeuroD pathway activity, the extinction of the opioid drug reward experience and subsequent drug relapse, can be regulated, and a future treatment paradigm can be developed. PUBLIC HEALTH RELEVANCE: With the recent increase in prescriptions written, leading to increased assess to opioids, elucidation of the mechanism in which long-term use of opioid medication leads to addiction and relapse, is critical. Upon completion, our studies will provide important information on whether, by regulating the various aspects of the differentiation and maturation of newborn neurons in the brain, the drug experience can be modulated. This information will be essential in the future development of eventual treatment paradigms for opioid addiction and relapse.